ClinVar Miner

Submissions for variant NM_000138.4(FBN1):c.2920C>T (p.Arg974Cys) (rs397514558)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000548224 SCV000627874 pathogenic Marfan syndrome; Thoracic aortic aneurysm and aortic dissection 2017-02-17 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 974 of the FBN1 protein (p.Arg974Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the literature co-segregating with disease in a family affected with isolated ectopia lentis (PMID: 22539873). It has also been reported in unrelated individuals affected with Marfan syndrome (PMID: 17657824, 17627385). ClinVar contains an entry for this variant (Variation ID: 39667). This variant generates a cysteine residue in an epidermal-growth-factor (EGF)–like domain of the FBN1 protein. Cysteine residues in these domains have been shown to be involved in the formation of disulfide bridges, which are critical for FBN1 protein structure and stability (PMID: 4750422, 16677079). Cysteine creating variants in these domains have been shown to affect protein stability and are overrepresented among individuals with Marfan syndrome (PMID: 15161917, 16571647, 17701892). For these reasons, this variant has been classified as Pathogenic.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000726909 SCV000704117 pathogenic not provided 2016-12-28 criteria provided, single submitter clinical testing
Ambry Genetics RCV000621942 SCV000738929 pathogenic Cardiovascular phenotype 2017-10-26 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Strong segregation with disease (lod >3 = >10 meioses),Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Rarity in general population databases (dbsnp, esp, 1000 genomes),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Center for Human Genetics, Inc RCV000032871 SCV000781346 pathogenic Marfan syndrome 2016-11-01 criteria provided, single submitter clinical testing
RBHT Clinical Genetics and Genomics Laboratory,Royal Brompton and Harefield NHS Foundation Trust RCV000032871 SCV000845663 likely pathogenic Marfan syndrome 2017-07-27 criteria provided, single submitter clinical testing The FBN1 c.2920C>T variant has previously been reported in 9 affected members of a 5 generation family with isolated ectopia lentis (Yang et al. Mol Vis. 2012;18:945-50) and a single patient with Marfan syndrome with major skeletal, ocular and cardiovascular manifestations (Comeglio et al. Hum Mutat. 2007 ;28(9):928). It has not been detected in approximately 120,000 individuals in control populations (gnomAD database). In silico tools predict the variant will adversely affect protein structure and function and it affects a highly conserved TGFB binding domain. This variant is therefore likely to be pathogenic, but may be associated with a variable phenotype. - Other Disease Reports - This variant has been linked to other diseases: Ectopia lentis (pubmed: 22539873) - Missense Effect Predictions - 87.5% (7/8) of algorithms have predicted that this variant will adversely affect protein function
OMIM RCV000032871 SCV000056641 pathogenic Marfan syndrome 2012-01-01 no assertion criteria provided literature only
OMIM RCV000172857 SCV000223833 pathogenic Ectopia lentis, isolated, autosomal dominant 2012-01-01 no assertion criteria provided literature only
Center for Medical Genetics Ghent,University of Ghent RCV000032871 SCV000786902 likely pathogenic Marfan syndrome 2017-11-07 no assertion criteria provided clinical testing

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